Lineage relationships of human interleukin-22–producing CD56+ RORγt+ innate lymphoid cells and conventional natural killer cells

Abstract

AbstractHuman interleukin (IL)-22–producing RORγt+ innate lymphoid cells (ILC22) and conventional natural killer (cNK) cells are present in secondary lymphoid tissues. Both have an immunophenotype corresponding to stage III NK progenitors (CD56+/−CD117highCD94−). Using an in vitro differentiation and primary human tissues, we investigated their developmental relationships. cNK cells showed a CD56+CD117+CD7+/−LFA-1high phenotype and expressed surface receptors, cytokines, and transcription factors found on mature cNK cells. In contrast, ILC22 cells were contained within the CD56+CD117highCD94−CD7−LFA-1− fraction and produced IL-22, IL-8, and granulocyte macrophage colony stimulating factor. Although ILC22 cells expressed NKp44 and CD161, they lacked most other NK receptors and NK-associated transcription factors (T-bet and Eomes) and were incapable of interferon-γ production or cytotoxic responses. Most purified CD56+CD117+CD7+/−LFA-1− remained as ILC22 cells and never became cNK cells. In the absence of IL-15, CD34+ cells showed a complete block in cNK differentiation and instead gave rise to a CD56+ population of ILC22 cells. Conversely, in the absence of IL-7 and stem cell factor, cNK cells were generated but ILC22 cells showed minimal differentiation. Although human ILC22 cells and cNK progenitors have a phenotype that overlaps with stage III NK progenitors, they have unique cytokine requirements and can be distinguished by LFA-1 expression.